The broad objective of this research is to apply the image-based fluid-structure interaction (FSI) technique to study the mechanical force resulting from the multiscale interactions between pulmonary gas flow and lung tissue mechanics, and its role in the distribution and progression of lung disease. A biological hypothesis motivating this work is that lung diseases alter mechanical force, which then alters stress-mediated adenosine triphosphate nucleotide release, disturbs periciliary liquid (PCL) water homeostasis, and weakens the integrated airway defense system, forming a vicious cycle of events. In a multidisciplinary effort, this proposal seeks to adopt an innovative systems biology approach that integrates mechanics and cell models to model transmittal of mechanical force from macro to micro scales, and further translation to biochemical responses at cellular level to maintain the PCL volume for mucociliary clearance. To achieve the objective and test the hypothesis, we propose the following specific aims. (1) Study the distributions of airflow-induced shear stress and airway-wall tissue stress in the central 6 generations of airways where the maximum resistance occurs. The emphasis will be placed on alteration of stresses due to airway rigidity, airway narrowing, and tissue stiffness, especially near the bifurcations in both upper and lower lobes as assessed in normal, asthmatic and emphysema subjects. (2) Study the biochemical responses of bronchial epithelial cells to the alteration of stresses in terms of the regional distributions of PCL water level and calcium ion concentration together with thermodynamics for heat and moisture in the human lung. The emphasis will be placed on deviation from PCL water homeostasis due to depletion or over-production of PCL volume near the bifurcations in both upper and lower lobes, and assess its implication on mucociliary transport. (3) Share the databases and models developed for this project with research and clinical communities via our medical image file archive system and model repository. To achieve these aims, we will extend our existing flow model to include lung tissue mechanics via image-registration-assisted FSI to simulate transmittal of mechanical force between airflow and tissue. We will also incorporate a stress-dependent nucleotide model into our existing model for calcium signaling and transmembrane ion and water fluxes in the ciliated epithelial cell. The fluid-structure (organ- tissue) mechanics model and the epithelial cell model will be integrated with regionally distributed airway thermodynamics to predict dynamic changes in the depth of the PCL layer and calcium ion concentration in the healthy and diseased airways. Both multi-detector row computed tomography (MDCT) experiments and cell culture experiments will be performed for model refinement and validation.